Fe2+ as a Physiological and Selective Inhibitor of Vitamin C-Induced Cancer Cell Death
High concentrations of ascorbic acid (AA) exert pro-oxidative actions and induce cancer cell death. Recent research on AA toxicity centers on the generation of H2O2, but it remains largely unknown why AA is toxic to cancer cells. In the present study we found that low concentrations (<10 μM) of Fe2+ inhibited the toxic effects of AA as well as those of isoascorbic acid (IAA), but not, as far as examined here, on any other types of cell death from H2O2, sodium nitroprusside (a NO donor), xanthine+xanthine oxidase (a superoxide inducer), A23187 (a Ca2+ ionophore), thapsigargin (an inducer of ER stress), staurosporine (a protein kinase inhibitor), cisplatin (an inducer of DNA damage), 5-fluorouracil (a DNA synthesis inhibitor), or actinomycin D (an RNA synthesis inhibitor) in COS7 cells. Fe2+ at concentrations of 1–10 μM inhibited the cell death caused by up to 5 mM AA. However, other divalent metal cations (Mn2+, Cr2+, Cu2+, Zn2+, Cd2+, and Ni2+) were not inhibitory, suggesting that just Fe2+, among divalent cations, had such an action on cancer cells at concentrations up to 100 μM. The Fe2+-inducedinhibition was commonly observed in COS7 (kidney cancer), Hela (uterine cancer), T98G (glioma), and PC-14 (lung cancer) cells, suggesting the inhibition to be a ubiquitous event among cancer cells. These results suggest that Fe2+ is a physiological and selective inhibitor of the AA-induced cancer cell death. The presence of high concentrations (around 30 μM) of Fe2+ in vivo might explain unstable effectiveness of AA and IAA infusions against various types of cancers. Conversely, a decrease in Fe2+ concentrations in vivo might potently enhance the therapeutic effects of AA infusion against various types of cancers.
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